Cisplatin, cis-[PtCl2(NH3)2], is one of the most widely used anti-tumor drugs. Cisplatin is a square-planar Pt (II) complex featuring two inert Pt—N bonds and two relatively labile Pt—Cl bonds. The electrophilic character of the central platinum atom allows cis-[PtCl2(NH3)2] to enter a cell to react with nucleophilic groups of the cellular components. A number of observations indicate that the anti-tumor activity of cisplatin is related to its ability to bind to DNA through sequential replacements of the chloride ligands by the N7 atoms of the guanine or the adenine bases.
The Physicians' Desk Reference reports that cisplatin (commercial name, Platinol) can be used to treat testicular, ovarian, and bladder cancers. Methods of treating cancer using cisplatin and cisplatin analogs are described in U.S. Pat. No. 4,177,263, among other publications. Cisplatin is administered intravenously and is transported throughout the body by the blood stream. Cisplatin reaches cancer cells mainly as a neutral molecule and is believed to enter the cell mainly through passive diffusion. Inside the cell, hydrolysis replaces one or both chlorines with water molecules (aquation). The intermediate monoaquated species, [PtCl(H2O)(NH3)2]+, is the most active/reactive species responsible for the cytotoxic action of cisplatin. The final product of cisplatin hydrolysis is [Pt(OH)2(NH3)2], which is inactive.
Cisplatin, although a very potent and successful antineoplastic, is very toxic. Nephrotoxicity and ototoxicity are dose-limiting factors, and other toxic manifestations include severe nausea and vomiting. The severe toxicity of cisplatin coupled with the development over time of cisplatin-resistant tumors has led to the search for, and development of, improved platinum-based drugs. Desired properties of new and improved platinum drugs include a broader spectrum of activity, particularly against cisplatin-resistant tumors (e.g., lung, breast, and colon cancers); an improved therapeutic index, either through greater efficacy or reduced toxicity; and/or modified pharmacological properties to improve drug delivery.
Several second generation platinum anti-cancer compounds, for example, carboplatin (cis-diamine[1,1-cyclobutanedicarboxylato(2-)]-O,O′-platinum (II)), oxaliplatin, iproplatin, and tetraplatin, have been developed. Carboplatin was the second platinum anticancer drug to be approved for clinical use and is less toxic than cisplatin. However, carboplatin is also less active against tumors, requiring higher dosing, and is affected by the same resistance mechanism. Iproplatin and tetraplatin are as active as carboplatin, but are more toxic. Oxaliplatin is more toxic than carboplatin, but has shown promising activity in gastrointestinal tumors, in patients with ovarian cancer who have previously received cisplatin, and in advanced, cisplatin-resistant non-small cell lung patients.
Limitations in second generation platinum drugs have led to the development of third generation compounds, including chelates containing 1,2-diaminocyclohexane (DACH), and promising non-classic (trans- and multinuclear) platinum complexes.
Multinuclear platinum compounds represent innovative structures designed and investigated with the aim of discovering new platinum compounds that are structurally dissimilar to cisplatin and possibly characterized by innovative mechanisms of DNA interaction. Various multinuclear platinum complexes with anti-cancer activity have been described and are currently in clinical trials. One example of a multinuclear platinum compound is BBR3464 (see U.S. Pat. No. 6,011,166; Manzotti et al., Cancer Res. 6:2626, 2000). In preclinical studies, BBR3464 exhibited a very high biological activity against cisplatin-resistant tumor cell lines, but toxic side effects were dose limiting. Fewer than 1% of the platinum complexes tested for pre-clinical anti-cancer activity have entered clinical trials in the past 20 years (Perez et al., Curr. Med. Chem.-Anti-Cancer Agents 2 (4): 539:551, 2002).
Accordingly, despite the advances that have been made in the development of alternative platinum compounds, there exists is a need in the art for platinum compounds that are as active as cisplatin, have lower toxicity than cisplatin, and that are effective against cisplatin resistant tumors.